Serine carboxypeptidases are a family of proteases found in vertebrate and invertebrate tissues that function in many physiological processes. These proteases remove a wide range of COOH-terminal amino acids, and in doing so are able to activate, inactivate, and modulate enzyme and peptide hormone activity. Many active forms of mammalian carboxypeptidases are located in lysosomes where they regulate intracellular protein processing, degradation and turnover. In plants and insects the serine carboxypeptidases play a role in posttranslational protein modifications including mobilization of storage proteins and hormone activation. The extensively characterized KEX1 yeast carboxypeptidase activates K1 and K2 killer toxins and alpha-factor (mating pheromone) by removing the lysine and arginine residues from the precursor forms. The carboxypeptidases exhibiting this enzymatic activity are distinguished by a common catalytic triad, Ser, His, and Asp residues, and are inhibited by serpins (Galjart, J. (1988) Cell 54: 755-764; Latchinian-Sadek, L. et al. (1994) Eur.J. Biochem. 219: 647-652; Elsliger, M. A. (1994) Proteins 18: 81-93).
Human lysosomal protective protein (HPP) is a serine carboxypeptidase with multiple biological properties. It functions as a protease with properties similar to cathepsin A at the acidic pH of lysosomes, and as an esterase or a carboxyl-terminal deamidase at neutral pH. HPP is similar to serine carboxypeptidases derived from insects, yeast and plants that are implicated in proteolytic activation of a number of enzymes or other biologically active molecules. It is synthesized as a 54-kDa precursor and can be processed into a catalytically active disulfide-linked 32 and 20-kDa heterodimer. The precursor dimerizes at neutral pH shortly after synthesis and is transported to the lysosome. The human enzyme, purified from platelets and lymphocytes, functions both in vitro and in vivo to inactivate selected signaling peptides, including substance P, oxytocin, neuropeptides, and endothelin I (Galjart, J., supra; Jackman, H. L. (1990) J. Biol. Chem. 265:11265-11272).
HPP is designated as `protective protein` when it forms a complex with lysosomal glycosidases, .beta.-D- galactosidase and N-acetyl-neuramidase (sialidase), and protects them from degradation. Complex formation serves to regulate enzyme activity within the lysosomes. An inherited metabolic disease, galactosialidosis, is caused by a genetic defect of in HPP, which results in a deficiency of lysosomal glycosidase activities. When the hydrolytic activity of these lysosomal glycosidases is compromised, heterogeneous neurosomatic manifestations result. Several HPP mutations have been identified for each clinical subtype, and a correlation has been shown between genotype and phenotype (Shimmoto, M., et al.(1993) J. Clin. Invest. 91: 2393-2398).
The vitellins, multisubunit phosphoglycoproteins, are stored in yolk granules and serve as a primary nutrient source for developing embryos. The vitellogenic carboxypeptidase, (VCP), hydrolyzes yolk proteins for utilization by the embryo during development. In mosquito (Aedes aegypti) VCP proenzyme is produced in extraovarian tissues, secreted into the hemolymph, and selectively internalized by developing oocytes where it accumulated in yolk bodies. It is activated at the onset of embryogenesis and is completely degraded by the time the first instar larvae hatch (Cho, W. L., et al. (1991) Proc. Natl. Acad. Sci. 88: 10821-10824).
The discovery of proteins related to human lysosomal protective protein and Aedes aegypti vitellogenic carboxypeptidase and the polynucleotides encoding them satisfies a need in the art by providing new compositions useful in diagnosis and treatment of disorders associated with expression of serine carboxypeptidases.